Hearing and balance disorders are some of the most common disabilities in the United States, with 0.1% of newborns having some form of hereditary hearing loss and roughly half of all adults suffering from some degree of hearing loss by the time they reach retirement age. The causes of age-dependent hearing loss are complex, with both genetic and environmental factors playing a role. Although progress has been made understanding the genes responsible for hearing and balance disorders in children and aging adults, there is still a great need for methods to identify new genes involved in ear dysfunction and degeneration. The fruit fly Drosophila has served as an outstanding model system for understanding the genetics of development and disease. Drosophila models have been established for a number of neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, Huntingdon's disease and amyotrophic lateral sclerosis, and these models have greatly assisted our understanding of the molecular basis for neurodegeneration. Recent genetic, physiological and biophysical data suggest that despite their great separation in evolutionary time, Drosophila and mammals share many similarities in the cellular and molecular mechanisms they use to detect sound and gravity. In this exploratory R21 project we propose to develop reagents that will allow us to perform high-throughput genetic screens for hearing and gravitaxis mutants in Drosophila. The long-term goal of this project is to use Drosophila to identify genes that affect the development and function of the mammalian auditory and vestibular systems, and genes that may influence the progression of age-dependent hearing loss. In this pilot project, we will first identify genetic tools ("Flp" lines of flies) that can be used to cause mutations specifically in the hearing organ of Drosophila. Second, we will verify these Flp lines can be used to cause defects in hearing and gravity sensation by crossing them with mutant lines know to cause defects in the hearing organ of Drosophila. Finally, we will begin a pilot screen of several hundred mutagenized Drosophila lines to identify mutants with defects in hearing and gravity sensation. PUBLIC HEALTH RELEVANCE: This project is to develop methods for identifying new genes that can cause hearing or balance defects in the fruit fly Drosophila. There is much evidence to suggest that genes involved in deafness in humans have equivalents in flies. The long term goal of this project is to use fruit flies to discover new deafness genes in humans and to understand how they affect hearing and balance in humans.